Unraveling the senses of Phytophthora; leads to novel control strategies?

Oomycetes cause devastating diseases on plants and animals. They cause major yield losses in many crop plants and their control heavily depends on agrochemicals. This is certainly true for the potato late blight pathogen Phytophthora infestans. Strong concerns about adverse effects of agrochemicals on food safety and environment are incentives for the development of novel, environmental friendly control strategies preferably based on natural products. Cyclic lipopeptides (CLPs) were recently discovered as a new class of natural compounds with strong activities against oomycetes including Phytophthora. CLPs lyse zoospores, inhibit mycelial growth and effectively reduce late blight disease. In order to unravel how Phytophthora senses CLPs and other environmental signals we follow two approaches. On the one hand, we monitor genome wide changes in gene expression induced by CLPs with the aim to identify the cellular pathways targeted by CLPs. On the other hand, we analyse components of ubiquitous signal transduction pathways with the aim to identify features that are unique for Phytophthora or oomycetes and, hence, could be suitable targets for novel anti-oomycete agents. Mining and comparing whole genome sequences have revealed that Phytophthora harbours many novel phospholipid modifying enzymes, unique for oomycetes. They have aberrant combinations of catalytic and regulatory domains occasionally combined with transmembrane domains. The latter resemble receptors that might be activated by extracellular ligands. Phospholipids, the substrates of these enzymes, are structural membrane components that also function in signalling. Together these findings open new avenues of research aimed at target-discovery in oomycetes

Identification of T. gondii myosin light chain-1 as a direct target of TachypleginA-2, a small-molecule inhibitor of parasite motility and invasion

This work was supported by US Public Health Service grant AI054961 (GEW/NJW), a University Research Fellowship from the Royal Society (NJW) and funding for the mass spectrometry analysis was provided by the Vermont Genetics Network/NIH Grant 8P20GM103449 from the INBRE program of the NIGMS.Motility of the protozoan parasite Toxoplasma gondii plays an important role in the parasite's life cycle and virulence within animal and human hosts. Motility is driven by a myosin motor complex that is highly conserved across the Phylum Apicomplexa. Two key components of this complex are the class XIV unconventional myosin, TgMyoA, and its associated light chain, TgMLC1. We previously showed that treatment of parasites with a small-molecule inhibitor of T. gondii invasion and motility, tachypleginA, induces an electrophoretic mobility shift of TgMLC1 that is associated with decreased myosin motor activity. However, the direct target(s) of tachypleginA and the molecular basis of the compound-induced TgMLC1 modification were unknown. We show here by ''click'' chemistry labelling that TgMLC1 is a direct and covalent target of an alkyne-derivatized analogue of tachypleginA. We also show that this analogue can covalently bind to model thiol substrates. The electrophoretic mobility shift induced by another structural analogue, tachypleginA-2, was associated with the formation of a 225.118 Da adduct on S57 and/or C58, and treatment with deuterated tachypleginA-2 confirmed that the adduct was derived from the compound itself. Recombinant TgMLC1 containing a C58S mutation (but not S57A) was refractory to click labelling and no longer exhibited a mobility shift in response to compound treatment, identifying C58 as the site of compound binding on TgMLC1. Finally, a knock-in parasite line expressing the C58S mutation showed decreased sensitivity to compound treatment in a quantitative 3D motility assay. These data strongly support a model in which tachypleginA and its analogues inhibit the motility of T. gondii by binding directly and covalently to C58 of TgMLC1, thereby causing a decrease in the activity of the parasite's myosin motor. Publisher PDFPeer reviewe

Innovative Technique for Below the Knee Arterial Revascularisation Using Porcine Self Made Stapled Pericardial Tube Grafts.

When no autologous vein is available for distal bypass in the setting of chronic limb threatening ischaemia (CLTI), new alternatives are required to solve the problems of availability, patency, and resistance to infection. An innovative technique of below the knee bypass for CLTI using a porcine self made stapled pericardial tube graft is reported. An 84 year old man, admitted with right CLTI with foot infection due to long occlusion of the femoropopliteal segment, required urgent revascularisation. In the absence of autologous vein and cryopreserved vessels, a 4 mm self made stapled porcine pericardial tube graft 56 cm long was created from two 14 × 8 cm patches, to perform a femorotibioperoneal trunk bypass. On day 10, bypass thrombectomy and balloon angioplasty of the distal anastomosis were needed to treat early occlusion. Oral anticoagulation was then started. Right toe pressure increased from 0 to 70 mmHg, and no infection was reported. Complete wound healing was achieved. At six months, the bypass was still patent. The use of porcine self made stapled pericardial tube grafts could offer new options for revascularisation in CLTI. Larger cohort studies with longer follow up are needed to confirm this successful preliminary experience

NGS-Based Diagnosis of Treatable Neurogenetic Disorders in Adults: Opportunities and Challenges.

The identification of neurological disorders by next-generation sequencing (NGS)-based gene panels has helped clinicians understand the underlying physiopathology, resulting in personalized treatment for some rare diseases. While the phenotype of distinct neurogenetic disorders is generally well-known in childhood, in adulthood, the phenotype can be unspecific and make the standard diagnostic approach more complex. Here we present three unrelated adults with various neurological manifestations who were successfully diagnosed using NGS, allowing for the initiation of potentially life-changing treatments. A 63-year-old woman with progressive cognitive decline, pyramidal signs, and bilateral cataract was treated by chenodeoxycholic acid following the diagnosis of cerebrotendinous xanthomatosis due to a homozygous variant in CYP27A1. A 32-year-old man with adult-onset spastic paraplegia, in whom a variant in ABCD1 confirmed an X-linked adrenoleukodystrophy, was treated with corticoids for adrenal insufficiency. The third patient, a 28-year-old woman with early-onset developmental delay, epilepsy, and movement disorders was treated with a ketogenic diet following the identification of a variant in SLC2A1, confirming a glucose transporter type 1 deficiency syndrome. This case study illustrates the challenges in the timely diagnosis of medically actionable neurogenetic conditions, but also the considerable potential for improving patient health through modern sequencing technologies

Glueballs, symmetry breaking and axionic strings in non-supersymmetric deformations of the Klebanov-Strassler background

We obtain an analytic solution for an axionic non-supersymmetric deformation of the warped deformed conifold. This allows us to study D-strings in the infrared limit of non-supersymmetric deformations of the Klebanov-Strassler background. They are interpreted as axionic strings in the dual field theory. Following the arguments of [hep-th/0405282], the axion is a massless pseudo-scalar glueball which is present in the supergravity fluctuation spectrum and it is interpreted as the Goldstone boson of the spontaneously broken U(1) baryon number symmetry, being the gauge theory on the baryonic branch. Besides, we briefly discuss about the Pando Zayas-Tseytlin solution where the SU(2) \times SU(2) global symmetry is spontaneously broken. This background has been conjectured to be on the mesonic branch of the gauge theory.Comment: 30 pages; V2: minor corrections; V3: section 3 corrected and misprints corrected to match version published in JHE

Acoustic Power Absorption and its Relation with Vector Magnetic Field of a Sunspot

The distribution of acoustic power over sunspots shows an enhanced absorption near the umbra--penumbra boundary. Earlier studies revealed that the region of enhanced absorption coincides with the region of strongest transverse potential field. The aim of this paper is to (i) utilize the high-resolution vector magnetograms derived using Hinode SOT/SP observations and study the relationship between the vector magnetic field and power absorption and (ii) study the variation of power absorption in sunspot penumbrae due to the presence of spine-like radial structures. It is found that (i) both potential and observed transverse fields peak at a similar radial distance from the center of the sunspot, and (ii) the magnitude of the transverse field, derived from Hinode observations, is much larger than the potential transverse field derived from SOHO/MDI longitudinal field observations. In the penumbra, the radial structures called spines (intra-spines) have stronger (weaker) field strength and are more vertical (horizontal). The absorption of acoustic power in the spine and intra-spine shows different behaviour with the absorption being larger in the spine as compared to the intra-spine.Comment: 18 pages, 7 figures, In Press Solar Physics, Topical Issue on Helio-and-Astroseismolog

Interacting fermions in self-similar potentials

We consider interacting spinless fermions in one dimension embedded in self-similar quasiperiodic potentials. We examine generalizations of the Fibonacci potential known as precious mean potentials. Using a bosonization technique and a renormalization group analysis, we study the low-energy physics of the system. We show that it undergoes a metal-insulator transition for any filling factor, with a critical interaction that strongly depends on the position of the Fermi level in the Fourier spectrum of the potential. For some positions of the Fermi level the metal-insulator transition occurs at the non interacting point. The repulsive side is an insulator with a gapped spectrum whereas in the attractive side the spectrum is gapless and the properties of the system are described by a Luttinger liquid. We compute the transport properties and give the characteristic exponents associated to the frequency and temperature dependence of the conductivity.Comment: 18 pages, 10 EPS figure